Veterinary products can be administered to warm-blooded animals in very different ways depending on their mode of action and their ability to be taken up either by the treated animal or the target pest. Thus veterinary products can be administered, for example, topically as pour-on or spot-on formulations, in form of shampoos, showers, as a dip, bath or spray, in form of a collar, and in many variants of these application forms. They can also be administered systemically, for example, orally, parenterally and in certain cases even transdermally. Examples of systemic administration forms are: via injection, as a tablet, capsule, bolus, drink, feed additive and the like. Each of these administration forms can have advantages or disadvantages depending on the actual situation and the animal that is in need of such a treatment. Treatment of herd animals, like horses, cattle, sheep or poultry usually requires different administration methods than for the treatment of single animals, such as pets like dogs and cats.
One very convenient and easy to manage administration form for human patients is the oral uptake of a medicament. This would also be very desirable in the field of veterinary medicine but here the animal holder or veterinarian is confronted with the natural behavior of the animal and oral treatment can be a real challenge.
Many attempts have been made to design the ideal oral application form that is really accepted and voluntarily taken up by the animal but most of these application forms need still to be improved.
The present inventors recognized that in the field of animal health the dosage form and especially the palatability of the dosage form, i.e. the natural acceptance of the drug plays the decisive role. The underlying problems are outlined hereinafter.
While, in humans, medicaments may be administered in a wide variety of application forms, such as tablets, coated tablets, emulsions, injection solutions, suppositories and the like, because the discipline and the desire to recover in human patients can be relied upon, in the case of animals practical problems are soon encountered, since a few application forms, such as the usage of suppositories, either have to be dispensed with all together or other forms, such as injections, must only be carried out by the veterinarian.
In general, humans do not like to visit the doctor. The same is true for animal keepers who would need advice from a veterinarian. In general, the animal keeper prefers to use those treatment methods that he can carry out himself without having involved a veterinarian. Among the preferred treatment methods, which an animal keeper can carry out himself, e.g. following the veterinarian's instructions, is the oral administration of medicaments.
Treating humans with medicines is generally not problematic, because the human patient follows the advice of the doctor or reads the directions on the leaflet in the package and complies with them since this is in his own interest, and because the manufacturer usually prepares the tablet, capsule or coated tablet in a form which is appropriate for oral consumption and has been tailored for human patients.
However, as soon as a pharmaceutical active ingredient has a taste which is unpleasant to the animal, whether because it is bitter or has some other unpleasant taste or is simply alien to the animal, the animal refuses to take it orally. This inborn behavior occurs to varying degrees among the different species of animals, and essentially depends on their conventional eating habits. Unfortunately, only a few active ingredients have a neutral taste, so that the problem being discussed here is almost always present.
In the case of a human patient, an unpleasant tasting active ingredient can be masked relatively easily, e.g. by coating it with a neutral-tasting or sweet layer. Everybody has come across gelatin capsules or tablets coated with sugar or lacquer at some time or other. It is easy to instruct the human patient to take the preparation without chewing.
An animal must have a natural willingness to take a medicinal preparation orally, which means that the medical preparation must taste well and be palatable. Of course, an individual animal or a few animals can also be forced to take a medicament, by making it swallow or by injecting it. However, such forced methods are not only unacceptable to large animal operations but also to single dogs and cats which tend to bite or scrape if they are not willing to be treated. This is why animal treatment can be very labor-intensive or can require the intervention of a veterinarian and this ultimately leads to increase of costs.
Therefore, for pets but equally for animals that are kept on a large scale, simple and safe oral application forms are required, which can be easily administered by the animal keeper, which lead to reliable results, and which are affordable.
The chewable composition according to the present invention is not only suitable for replacing the treatment with a tablet or capsule. These chewables can also easily be mixed with conventional non-medicated feed pellets if herds of animals have to be treated.
Due to their excellent palatability the chewables according to the present invention are taken up by animals without causing any acceptance problems. Their handling is easy and safe, and can be adapted to the need either of an individual animal like a cat or a dog or to a herd animals like sheep and cows.
When reviewing the administration of capsules and coated tablets to animals, it has been shown that these application forms are rather unsuitable for animal medicine, since in the case of herd animals they can only be used in a controlled manner with considerable effort on a daily basis, and in the case of pets, such as dogs and cats, lead to particular acceptance problems. As already mentioned above, the eating habits of animals generally play a decisive role when using oral application forms. Thus, most important is an attractive taste and the palatability.
In the case of dogs, it has been observed that they gnaw at solid food, e.g. on bones, and gulp down other food, either in the form of large scraps or wet formulated food, almost unchewed. If a tablet or coated tablet is mixed with the wet formulated feed, varying results are obtained. In a few cases, the tablet is not noticed by the dog at all and is simply gulped down, and in other cases it remains uneaten in the dog bowl. In contrast to dogs, cats are considerably more fastidious in their eating habits. Only in the rarest cases can a tablet or coated tablet be mixed with the formulated food, without them noticing it immediately and rejecting it. Although cats also to not exactly chew their food, they generally break it down with a few small bites. They thereby damage the protective coating of a tablet or capsule and release the unpleasant tasting active ingredient. Attempts to mix the active ingredient directly with the feed likewise fail, because either the degree of dilution is insufficient to neutralize the unpleasant taste or the active ingredient breaks down too rapidly when in contact with the feed. For the same reasons, mixtures of feed, active ingredient and excipients, which should stimulate the appetite of dogs and cats, similarly do not have a successful outcome with cats. Whereas the test animals rush eagerly to a placebo which has a corresponding appetite stimulant, i.e. a tablet consisting of feed, flavoring and other excipients, but no active ingredient, the test animals reject the same combination as soon as active ingredient is added. Clearly, a different technical solution must be found to the existing problem with animals.
Of course, any other active ingredient which is suitable for animals can be administered according to the present invention, but especially those active ingredients that have the taste disadvantages mentioned initially and are therefore not willingly taken orally by animals.
Basically, a diversity of individual active ingredients or mixtures of active ingredients may be considered, e.g. those acting against external (ecto) or internal (endo) parasites or active ingredients acting against animal diseases including viral or bacterial infections, behavioral disorders, such as hypo- or hyper-activity, inflammatory diseases, and auto-immune diseases. Thus, the active ingredient can be a pesticide or a medicament or a mixture of both.
It should be kept in mind that the present invention deals with an optimized application form for veterinary compositions rather than with the treatment of animals with a specific class of active ingredients. On the contrary, the present invention provides an easy-to-use, safe, powerful, and stable veterinary formulation consisting of a highly palatable ductile chewable veterinary composition, which allows to administer orally almost each and any active ingredient to a warm-blooded animal, provided that this active ingredient or mixture of active ingredients is at the administered dose physiologically acceptable to the animal, does not display unacceptable side effects and, what is most important, exhibits after oral uptake systemic activity. This means that the main prerequisite for the active ingredient is that after oral administration it is taken up by the body fluids, including blood and lymph, and transported to the animal pest, the pathogen or the diseased organ where it can exhibit its activity. Thus, any active ingredient or class of active ingredients mentioned hereinafter is nothing but a non-limiting example of suitable active ingredients. The application form of the present invention is actually not limited to existing active ingredients but also suitable for each and any active ingredient developed in the future provided that the future active ingredient meets the main characteristics explained hereinbefore.
The highly palatable ductile chewable veterinary composition of the present invention is in principle a medicated food product and everybody working in this area is aware of the technical problems that arise in context with the production of medicated feed. For example, stability of the active ingredient is very crucial. It is a matter of fact that many potent active compounds are somewhat unstable (temperature-sensitive), above all when in contact with feed material, especially close contact to vegetable and animal materials, during conventional extrusion of feed pellets, result in considerable losses of active ingredient.
For example, when feed pellets are prepared via extrusion, the dried organic starting material of animal or vegetable origin is ground, is intimately mixed with the active ingredient, that is to say is substantially homogenized, and then is moistened with water or steam and is compressed into pellets at elevated temperatures and under pressures of around 100 kbar. However, said high pressures and the permanent high temperatures in the range of 60-100° C. are disadvantageous and do not only dramatically reduce the viscosity of the pellets but result in a considerable lost of active ingredient.
Whereas most active ingredients in pure form or in contact with carriers that are routinely used in the production of tablets or capsules withstand such relatively high temperatures per se very well and can be stored in pure form or as tablets or capsules at room temperature for months or years without any measurable loss of active ingredient, they decompose relatively rapidly under pressure and in intimate contact with animal or vegetable fibers in feedstuffs and under the prevailing elevated temperatures. It appears that contact with the fibers actually catalyses the decomposition process. Even when the elevated-pressure and elevated-temperature phase is kept as short as technically possible and the finished pellets are immediately cooled down to room temperature directly after the compression process, a quarter to a third of the active ingredient is nevertheless lost. Even though in the rare cases where the degradation products do not have disadvantageous effects on the animals treated, the unavoidable loss of active ingredient inevitably results in a considerable increase in the cost of the final product. Thus extrusion processes can lead to very undesirable effects.
For the reasons mentioned, therefore, much effort has been directed at stabilizing temperature-sensitive active ingredients so that they withstand the elevated temperatures and pressures during pellet preparation without loss of active substance and also, when in the form of the finished pellets, have a long-term storage stability suitable for practical purposes.
Unsuccessful attempts at such stabilization include, for example, (1) reduction of the active ingredient surface area by means of compression into granules, a very great variety of granule sizes having been tried; (2) sealing of the said active ingredient granules in a very great variety of protective layers, for example gelatin or various sugars and coatings; (3) enclosure of the active ingredient within porous materials such as, for example, various celluloses, starches, silicic acids or zeolites, with or without additional protective layers; and (4) chemical modification of the basic macrocyclic structure of the active ingredient. Although in a few cases chemical modification has resulted in improved stability of the compound per se, it has simultaneously resulted in loss of activity.
However, none of those attempts has resulted in an appreciably smaller loss of active ingredient on compression into feed pellets or in measurably improved storage stability.
Moreover, success has now been achieved, surprisingly, in providing the user with the user-friendly, easy-to-use, safe, powerful, stable, and especially highly palatable chewable veterinary composition of the present invention.
Astonishingly, it is now possible to provide a product that not only withstands the extrusion process undamaged but also survives for a outstanding long storage period.
Therefore, it is highly surprising and was absolutely unpredictable that even so the chewable veterinary composition of the present invention contains a relatively high amount of meat material, this has obviously when combined with the appropriate amount of partially gelatinized starch, no adverse effect on the stability of the active ingredient. It actually turned out that the chewable veterinary composition of the present invention is a very stable product that can be stored at room temperature over many months without significant loss or degradation of active ingredient. Tests with stored material demonstrate that the palatability is not decreased and the efficacy of the active ingredient stays at a high level.
Moreover, investigations of the kinetic behavior demonstrate another surprising effect. It could not have been foreseen that the administration of the chewable veterinary composition of the present invention could lead to absolutely the same level of bioavailability as the administration of tablets or capsules. Thus, the present invention provides a safe, easy to use and stable product that is at least as efficacious as conventional oral application forms, like tablets or capsules.
Many biocides and veterinary medicines that may be now be incorporated into the chewable veterinary composition and be used according to the present invention, have been known to skilled specialists for a long time but the conventional oral dosage forms are not satisfactory because they are not attractive for animals and show the disadvantages discussed above.
With the chewable veterinary composition of the present invention one can combat all kinds of parasites. External parasites, also called ecto-parasites, are understood to be parasites which normally live on the animal, i.e. an the animal's skin or in the fur. Enclosed are biting insects, such as mosquitoes, blowfly, fleas or lice, or members of the order Acarina, e.g. mites or ticks. Suitable products against external parasites include insecticides and acaricides. It does not matter what their mode of action actually is. They can be e.g. chitin synthesis inhibitors, growth regulators; juvenile hormones; adulticides. They can be broadband insecticides, broad-band acaricides. The active ingredient can be a killer or a deterrent or repellent. It can affect e.g. only adult stages or juvenile stages of the parasite or may affect any stage. The only prerequisite is that the active ingredient acts systemically. This means that it is not decomposed after oral uptake but transported by the body fluids to the skin or organ where the parasite uses to live.
If the active ingredient is an acaricide one can, for example, select a systemically acting acaricide from one of the following well-known classes of acaricides including: antibiotic acaricides such as abamectin, doramectin, eprinomectin, ivermectin, milbemectin, nikkomycins, selamectin, tetranactin, and thuringiensin; bridged diphenyl acaricides such as azobenzene, benzoximate, benzyl benzoate, bromopropylate, chlorbenside, chlorfenethol, chlorfenson, chlorfensulphide, chlorobenzilate, chloropropylate, dicofol, diphenyl sulfone, dofenapyn, fenson, fentrifanil, fluorbenside, proclonol, tetradifon, and tetrasul; carbamate acaricides such as benomyl, carbanolate, carbaryl, carbofuran, fenothiocarb, methiocarb, metolcarb, promacyl, and propoxur; oxime carbamate acaricides such as aldicarb, butocarboxim, oxamyl, thiocarboxime, and thiofanox; dinitrophenol acaricides such as binapacryl, dinex, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinopenton, dinosulfon, dinoterbon, and DNOC; formamidine acaricides such as amitraz, chlordimeform, chloromebuform, formetanate, and formparanate, mite growth regulators such as clofentezine, dofenapyn, fluazuron, flubenzimine, flucycloxuron, flufenoxuron, and hexythiazox; organochlorine acaricides such as bromocyclen, camphechlor, dienochlor, and endosulfan; organotin acaricides such as azocyclotin, cyhexatin, and fenbutatin oxide; pyrazole acaricides such as acetoprole, Fipronil and analogues and derivatives thereof, tebufenpyrad, and vaniliprole; pyrethroid acaricides including: pyrethroid ester acaricides like acrinathrin, bifenthrin, cyhalothrin, cypermethrin, alpha-cypermethrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate, tau-fluvalinate, and permethrin, and pyrethroid ether acaricides like halfenprox; quinoxaline acaricides such as chinomethionat and thioquinox; sulfite ester acaricides such as propargite; tetronic acid acaricides such as spirodicofen; and from unclassified acaricides such acequinocyl, amidoflumet, arsenous oxide, chloromethiuron, closantel, crotamiton, diafenthiuron, dichlofluanid, disulfiram, fenazaflor, fenazaquin, fenpyroximate, fluacrypyrim, fluenetil, mesulfen, MNAF, nifluridide, pyridaben, pyrimidifen, sulfiram, sulfluramid, sulfur and triarathene.
Suitable insecticides acting either as adulticides or insect growth regulators (IGRs) can be chosen from a variety of well-known different chemical classes such as chlorinated hydrocarbons, organophosphates, carbamates, pyrethroids, formamidines, borates, phenylpyrazoles, and macrocyclic lactones (previously known as avermectins). Prominent representatives of adulticides/insect killers are imidacloprid, fenthion, fipronil, allethrin, resmethrin, fenvalerate, permetrin, malathion and derivatives thereof. Insect adulticides kill the insect in almost any development stage either by contact or as a stomach poison. Widely used representatives of insect growth regulators (IGRs) are, for example benzoylphenylureas such as diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron, and teflubenzuron or substances like fenoxycarb, pyriproxifen, methoprene, kinoprene, hydroprene, cyromazine, buprofezin, pymetrozine and derivatives thereof. Insect growth inhibitors or insect growth regulators (any of which is commonly known as an IGR) are products or materials that interrupt or inhibit the life cycle of a pest.
It goes without saying that the highly palatable ductile chewable veterinary composition according to the present invention is also very suitable for administering active ingredients that combat internal parasites (endo-parasites) such as worms living in the blood or in organs of the animal. Thus, the active ingredient can be an anthelmintic (dewormer).
Anthelmintics (dewormers) are a heterogeneous group of drugs but they are selectively toxic to worms. The drugs can achieve this by either inhibiting the metabolic process vital to the parasite, or by causing the parasite to be exposed to higher concentration of drug than are the hosts cells, which means that one makes use of the existence of an advantageous therapeutic window. Anthelmintics can affect the target parasite during treatment by interfering with the integrity of parasite cells, inhibiting neuromuscular transmission and coordination, or mechanisms which protect against host immunity, that ultimately lead to the starvation, neuromuscular paralysis, death and expulsion of the parasite. Anthelmintics are commonly administered by drench, paste, orally, or by injection. The drugs are absorbed into the blood stream and widely diffused. They are metabolized in the liver and excreted in feces and urine. In the animal health field anthelmintics are used widely used against roundworms, lungworms, tapeworms, intestinal worms, whipworms, hookworms, pinworms, trichinella (trichinosis), and other less common organisms, liver flukes and other less common organisms in a broad range of animals such as beef, cattle, swine, goats, horses, and pets like cats and dogs. The activity spectrum of anthelmintics for dogs and cats embraces Trematodes such as Alaria alata and Opisthorchis tenuicollis; Cestodes such as Taenia hydatigena, Taenia pisiformis, Taenia ovis, Hydatigena Taenla taeniaeformis, Echinococcus granulosus, Echinococcus multilocularis, Dipylidium caninum, Diphyliobothrium latum, Multiceps multiceps, Multiceps serialis, Mesocestoides lineatus, and Mesocestoides corti; and Nematodes such as Ancylostoma caninum, Uncinaria stenocephaia, Toxocara canis, Toxocara cati, Toxascaris leonina, Strongyloides stercoralis, Filaroides osieri, Capillaria aerophila, Capillaria plica, Capillaria hepatica, Trichinella spiralis, Angiostrongylus vasorum, Trichuris vulpis, Spirocerca lupi, Dirofilaria immitis, Ancylostoma tubaeforme, and Aelurostrongylus abstrusus. 
Internal parasites within the present invention include all species of worm infestation (helminthes) but also bacteria and viruses causing bacterial and viral infections, in particular those that infest the organs or parts of the body, such as the lungs, heart, alimentary tract or extremities, or which spread through the whole organism.
The anthelmintic can be selected from endo-parasiticides and endecticides including one of the following well-known groups of dewormers such as macrocyclic lactones (sometimes called simply macrolides), benzimidazoles, pro-benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
A most preferred group of anthelmintics consists of the more modern natural or chemically modified macrocyclic lactones (macrolides), such as avermectins, milbemycins and derivatives thereof, including prominent representatives such as Ivermectin, Doramectin, Moxidectin, Selamectin, Emamectin, Eprinomectin, Milbemectin, Abamectin, Milbemycin oxime, Nemadectin, and a derivative thereof, in free form or in the form of a physiologically acceptable salt.
The macrocyclic lactones are most preferred because they exhibit a broad spectrum of activity. Most of them exhibit ecto and in parallel endo-parsiticidal activity. Therefore, they are also called endectocides. Macrocyclic lactones bind to glutamated chlorine channels causing in the first instance paralysis and later on the death of the parasite.
In the context of the invention, a preferred group of macrocyclic lactones is represented by compounds of formula (I)
wherein X is —C(H)(OH)—; —C(O)—; or —C(═N—OH)—; Y is —C(H2)—; ═C(H)—; —C(H)(OH)—; or —C(═N—OCH3)—; R1 is hydrogen or one of radicals
R4 is hydroxyl, —NH—CH3 or —NH—OCH3; R2 is hydrogen, —CH3, —C2H5, —CH(CH3)—CH3, —CH(CH3)—C2H5, —C(CH3)═CH—CH(CH3)2 or cyclohexyl; and if the bond between atoms 22 and 23 represents a double bond the carbon atom in 23-position is unsubstituted so that Y is ═C(H)—, or if is the bond between atoms 22 and 23 is a single bond the carbon atom in 23-position is unsubstituted or substituted by hydroxy or by the group ═N—O—CH3 so that Y is —C(H2)—; —C(H)(OH)—; or —C(═N—OCH3)—; in free form or in the form of a physiologically acceptable salt.
Typical and especially preferred representatives of compounds of formula (I) are:    1) Ivermectin is 22,23-Dihydroabamectin; 22,23-dihydroavermectin B 1; or 22,23-dihydro C-076B 1, wherein X is —C(H)(OH)—; Y is —C(H2)—; R1 is the radical
     R2 is either —CH(CH3)—CH3 or —CH(CH3)—C2H5 and the bond between atoms 22 and 23 represents a single bond. Ivermectin is known from U.S. Pat. No. 4,199,569.    2) Doramectin is 25-Cyclohexyl-5-O-demethyl-25-de(1-methylpropyl)avermectin A 1a, wherein X is —C(H)(OH)—; Y is ═C(H)—; R1 is the radical
     R2 is cyclohexyl and the bond between atoms 22 and 23 represents a double bond. Doramectin is known from U.S. Pat. No. 5,089,480.    3) Moxidectin, is [6 R, 23 E, 25 S (E)]-5-O-Demethyl-28-deoxy-25-(1,3-dimethyl-1-butenyl)-6,28-epoxy-23-(methoxy imino)milbemycin B, wherein X is —C(H)(OH)—; Y is —C(═N—OCH3)—; R1 is hydrogen; R2 is —C(CH3)═CH—CH(CH3)2; and the bond between atoms 22 and 23 represents a single bond. Moxidectin, is known from EP-0,237,339 and U.S. Pat. No. 4,916,154.    4) Selamectin is 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)avermectin B1 monosaccharide and thus a compound of formula (I), wherein X is —C(═N—OH)—; Y is —C(H2)—; R1 is the radical
     R2 is cyclohexyl; and the bond between atoms 22 and 23 represents a single bond. Selamectin is known e.g. from: ECTOPARASITE ACTIVITY OF SELAMECTIN; A novel endectocide for dogs and cats. A Pfizer Symposium, held in conjunction with The 17th international Conference of the World Association for the Advancement of Veterinary Parasitology, 19 Aug. 1999. Copenhagen, Denmark.    5) Emamectin is (4primeprime R)-5-O-demethyl-4primeprimedeoxy-4primeprime-(methlamino)avermectin A 1a and (4primeprime R)-5-O-demethyl-25-de(1-methylpropyl)-4primeprime-deoxy-4primeprime-(methylamino)-25-(1-methylethyl)avermectin A 1a (9:1), wherein X is —C(H)(OH)—; Y is ═C(H)—; R1 is
     R2 is —CH(CH3)—CH3, or —CH(CH3)—C2H5, and the bond between atoms 22 and 23 represents a double bond. Emamectin is known from U.S. Pat. No. 4,874,749.    6) Eprinomectin is (4primeprime R)-4primeprime-epi-(acetylamino)-4primeprime-deoxyavermectin B 1, wherein X is —C(H)(OH)—; Y is ═C(H)—; R1 is the radical
     R2 is —CH(CH3)—CH3, or —CH(CH3)—C2H5, and the bond between atoms 22 and 23 represents a double bond. Eprinomectin is known from U.S. Pat. No. 4,427,663.    7) Milbemectin is (6R,25R)-5-O-demethyl-28-deoxy-6,28epoxy-25-methylmilbemycin, wherein    X is —C(H)(OH)—; Y is —C(H2)—; R1 is hydrogen; R2 is —CH3, or —C2H5; and the bond between atoms 22 and 23 represents a single bond. Milbemectin is known from U.S. Pat. No. 3,950,360.    8) Abamectin is Avermectin B 1 which is also named 5-O-demethylavermectin A 1a and 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)avermectin A 1a (4:1), wherein X is —C(H)(OH)—; Y is ═C(H)—; R1 is the radical
     R2 is —CH(CH3)—CH3, or —CH(CH3)—C2H5; and the bond between atoms 22 and 23 represents a double bond. Abamectin is known from U.S. Pat. No. 4,310,519.    9) Milbemycin oxim is milbemycin A 4 5-oxime; milbemycin A 3 5-oxime, wherein X is —C(H)(OH)—; Y is —C(H2)—; R1 is hydrogen; R2 is —CH(CH3)—CH3, or —CH(CH3)—C2H5, and the bond between atoms 22 and 23 represents a single bond. Milbemycin oxim is known from U.S. Pat. No. 4,547,520.    10) The compound of the formula (I) wherein X is —C(H)(OH)—; Y is —C(H2)—; R1 is the radical
     R2 is —CH3 or C2H5, and the bond between atoms 22 and 23 represents a single bond. This compound is known from WO 01/83500.    11) Nemadectin is antibiotic S-541A; also named [6 R, 23 S, 25 S,(E)]-5-O-Demethyl-28-deoxy-25-(1,3-dimethyl-1-butenyl)-6,28-epoxy-23-hydroxymilbemycin B; wherein X is ═CH—OH; Y is —C(H2)—; R1 is hydrogen; R2 is —C(CH3)═CH—CH(CH3)2, and the bond between atoms 22 and 23 represents a single bond. Nemadectin is known from U.S. Pat. No. 4,869,901.
The compounds specifically mentioned under items 1-11 hereinbefore, are preferred embodiments of the present invention and can be used either alone or in combination with another endo-parasiticide, ecto-parasiticide or endecticide.
Benzimidazoles, benzimidazole carbamate and pro-benzimidazoles interfere with energy metabolism by inhibition of polymerization of microtubules and include very potent compounds such as thiabendazole, mebendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, luxabendazole, netobimin, parbendazole, flubendazole, cyclobendazole, febantel, thiophanate and derivatives thereof.
Imidazothiazoles are cholinergic agonists and include highly active compounds such as tetramisole, levamisole, and derivatives thereof.
Tetrahydropyrimidines act are also cholinergic agonists and include highly active compounds such as morantel, pyrantel, and derivatives thereof.
Organophosphates are inhibitors of cholinesterase. This class includes potent compounds such as dichlorvos, haloxon, trichlorfon, and derivatives thereof.
Piperazines exhibit anticholinergic action and block neuromuscular transmission. This class includes highly active compounds such as piperazine and derivatives thereof.
Salicylanilide selected from closantel, tribromsalan, dibromsalan, oxychlozanide, clioxanide, rafoxanide, brotianide, bromoxanide and derivatives thereof.
Within the present invention the anthelmintic (dewormer) a preferred embodiment consist of a combination of a macrocyclic lactone and an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozanide, Oxibendazole, Oxfendazole, Oxfendazole, Oxamniquine, Pyrantel, Piperazine, Praziquantel, Thiabendazole, Tetramisole, Trichlorfon, Thiabendazole, and derivatives thereof. Most preferred is Praziquantel. In order to broaden the activity spectrum towards ecto-parasites said anthelmintic combination can contain in addition to the dewormers a parasiticidally effective amount of an insecticide, acaricide or an insecticide and an acaricide. Of course one could also add an antibiotic for treating bacterial disease.
All of the suitable parasiticides mentioned hereinbefore are known. Most of them are described in THE MERCK INDEX 1999 by Merck & Co Inc, Whitehouse Station, N.J., USA; published on CD-ROM by Chapman & Hill/CRC, 1999, Hampden Data Service Ltd. and in the literature specifically mentioned in THE MERCK INDEX 1999.
Suitable antimicrobial active ingredients are, e.g. various penicillins, tetracyclines, sulfonamides, cephalosporins, cephamycins, aminoglucosids, trimethoprim, dimetridazoles, erythromycin, framycetin, fruazolidone, various pleuromutilins such as thiamulin, valnemulin, various macrolides, streptomycin and substances acting against protozoa, e.g. clopidol, salinomycin, monensin, halofuginone, narasin, robenidine, etc.
Behavioral disorders include e.g. separation worry or travel sickness of dogs and cats. A suitable compound acting against behavioral disorders is e.g. clomipramine.
The chewable combination according to the present invention may also contain an active ingredient for the treatment of disfunctions or hypo-activity.
Dysfunction or hypo-activity is understood to include functions like autoimmune disorders, which deviate from the norm, whether through inborn or acquired damage to individual organs or tissue. This complex also includes rheumatic diseases, pathological changes to joints, bones or internal organs, and much more. A prominent representative of compounds that can be used in this complex area is cyclosporine and derivatives thereof. The term “animal disease” even includes different types of cancer and metastasis progression in connective tissues that are common in animals. In this field bisphosphonates like coledronate, clodronate, etidronate, pamidronate and alendronate play an important role. Said bisphosphonates can also be administered in the treatment or prophylaxis of ulcers, rheumatoid arthritis and other arthitides, and periodontitis. Another suitable class of active ingredients encompasses anti-inflammatory agents such as benzenesulfonamides like Deracoxib, which is extremely suitable for the control of pain and inflammation associated with osteoarthritis. Further anti-inflammatory agents are diclofenac and derivatives thereof.
In the present invention, the administration problems depicted in connection with conventional oral dosage forms, like tablets and capsules, can be very easily resolved and chewable products can be prepared, which are taken orally by the animals without causing any problems. The animals actually take the chewable veterinary composition voluntarily.